The present invention relates to biomaterials comprising an extirpated piece from Chondrichthyes, Osteichthyes or Cyclostomata. More specifically, the present invention relates to biomaterials that comprise the above extirpated piece and are applicable as various alternative organs and implant materials.
It has been considered difficult to achieve a successful xenogeneic transplantation between different kinds of animal in view of major histocompatibility complex (MHC) which causes the rejection reaction in the transplantation.
The inventor of the present invention has found that although a primitive vertebrate including Chondrichthyes, Cyclostomata and a part of Osteichthyes has a gene encoding MHC, the primitive vertebrate is in a state of immunological tolerance as seen in an embryo of a higher animal. The difference between the primitive vertebrate and the higher animal may be explained as follows: the expression of MHC gene was induced by an increased blood pressure caused in response to the gravity during the second revolution of vertebrates in the evolutionary process (i.e. terrestrialization), thereby generating human leukocyte antigen (HLA) in the course of evolution. As a result, the rejection reaction can be caused in the xenogeneic transplantation.
The inventor also has found that a skin transplantation between sharks as well as between shark and Cyclostomata can be successfully carried out, which had been considered impossible for a long time. In addition, it is also possible to transplant various organs from sharks to mammals.
The sharks have a much lower blood pressure whereas the mammals have a higher one because the sharks, in which the gravity is offset by buoyancy, differ from the mammals in responding to the gravity. Various organs from the shark may be transplanted to the mammals without any need for angiorrhaphy.
A series of studies shows that a primitive vertebrate is composed of the proteins that are closely similar to fetal proteins of the mammals. Various tissues from the primitive vertebrate have been observed to smoothly replace the mammal""s own tissues after transplantation.
In the case of human, a successful transplantation has been achieved only with allograft of organs between a recipient and a donor compatible with the recipient in histocompatibility antigen. According to the present invention, it is possible to use various tissues from the primitive vertebrate (e.g. viscus, nerve and cornea) for transplantation in human, so that an important contribution can be made to the progress of medical science.
The present application encompasses the following inventions:
(1) A biomaterial comprising an extirpated piece from a tissue selected from the group consisting of the cornea, muscle, tendon, cartilage, alimentary canal, liver, pancreas, spleen, kidney, heart, blood vessel, nerve and brain of Chondrichthyes, Osteichthyes or Cyclostomata;
(2) The biomaterial according to (1), wherein the extirpated piece is obtained from a tissue of Chondrichthyes or Osteichthyes;
(3) The biomaterial according to (1), wherein the extirpated piece is obtained from a tissue of Chondrichthyes;
(4) The biomaterial according to (1), which is transplanted into mammals; and
(5) The biomaterial according to (1), which is selected from the group consisting of an artificial cornea, an artificial muscle tissue, an artificial tendon, an artificial cartilage, an artificial alimentary canal tissue, an artificial liver tissue, an artificial pancreas tissue, an artificial spleen tissue, an artificial kidney tissue, an artificial heart tissue, an artificial blood vessel, an artificial nerve tissue and an artificial brain tissue.
Fishes to be used for obtaining an extirpated piece for preparing the biomaterials of the present invention may be Chondrichthyes, Osteichthyes or Cyclostomata.
As Chondrichthyes, fishes belonging to Elasmobranchii such as sharks and rays are preferred. Among all, sharks are most preferred. Specific examples of sharks include Shirozame, Mustelus, Triakis (dochizame) and Heterodontus(nekozame). Specific examples of rays include Anacanthobatis, Dasyatis and Pristis.
The Osteichthyes includes fishes having an endoskeleton, at least a part of which is bony, and a skull coated with periosteum. Fishes belonging to the Osteichthyes are roughly divided into large fishes and small fishes. Specific examples of large Osteichthyes include tuna, bonito and sea bass. Specific examples of small Osteichthyes include salmons such as Shirozake; sea breams such as Pagrus and Oplegnathus; red snappers such as Beryx and Anomalops; flatfishes such as Limanda and Engyprosopon; Seriola(yellowtail and young yellowtail) or Clupea.
The Cyclostomata includes fishes belonging to Agnatha including Petromyzontiformes and Myxiniformes. Specific examples include Lampetra japonica, Myxine and Eptatretus.
The extirpated piece used for preparing the biomaterials of the present invention may be taken from the following tissues or organs of these fishes: cornea, muscle, tendon, cartilage, alimentary canal, liver, pancreas, spleen, kidney, heart, blood vessel, nerve and brain.
The cornea used for the present invention may be taken from one or both of eyes of the Chondrichthyes and Osteichthyes (small one), and transplanted to each eye of mammals. A muscle used for the present invention may be, for example, a dorsal muscle of the Chondrichthyes. A tendon used for the present invention may be, for example, a fin of the Chondrichthyes. A cartilage used for the present invention may be, for example, a vertebral cartilage of the Chondrichthyes or an intervertebral cartilage of the Osteichthyes (large one). As an alimentary canal used for the present invention, for example, a part from the stomach to intestine may be used. In the case of the liver, for example, a hepatic parenchymal tissue from the Chondrichthyes may be implanted into the mammal""s liver including the human liver by incision. In the case of the pancreas, for example, the pancreas from the Chondrichthyes may be implanted into the mammal""s spleen or pancreas by incision. In the case of the spleen, for example, the spleen from the Chondrichthyes or Osteichthyes may be implanted into the spleen of a patient affected with blood disease by incision. In the case of the kidneys, for example, one or both of the kidneys from the Chondrichthyes may be implanted into a mammal""s renal parenchymal tissue by incision. In the case of the heart, the recipient""s heart from which a damaged part has been removed may be covered and sewn with the heart, for example, from the large Osteichthyes or Chondrichthyes. In the case of a nerve or the brain, the spinal cord from the Cyclostomata or Chondrichthyes may be transplanted as an alternative to nerve, or the brain from the Chondrichthyes may be transplanted to mammals. As an alternative to a blood vessel, for example, the alimentary canal from the Chondrichthyes or Cyclostomata may be used, from which an inner epithelial mucosa has been removed and which is turned over before used.
These extirpated pieces from the Chondrichthyes, Osteichthyes and Cyclostomata are preferred because there is no blood group substance or major histocompatibility antigen (i.e. no antigenicity) in these extirpated pieces including the cornea, muscle, tendon, cartilage, alimentary canal, liver, pancreas, spleen, kidney, heart, blood vessel, nerve and brain.
The biomaterials of the present invention may be used as an artificial tissue or organ including an artificial cornea, an artificial muscle tissue, an artificial tendon, an artificial cartilage, an artificial alimentary canal tissue, an artificial liver tissue, an artificial pancreas tissue, an artificial spleen tissue, an artificial kidney tissue, an artificial heart tissue, an artificial blood vessel, an artificial nerve tissue and an artificial brain tissue.
The term xe2x80x9cartificial tissue or organxe2x80x9d used here refers to a tissue or organ derived from organisms that can be used as an alternative to at least a part of a tissue or organ in a transplant recipient.
In the case of the artificial cornea, the cornea of Chondrichthyes (e.g. shark) or a small Osteichthyes can be used as an alternative to a mammalian denatured cornea. In the case of the artificial muscle tissue, a dorsal muscle of Chondrichthyes (e.g. shark) or Cyclostomata can be used for replacing an injured muscle, filling a defect in muscles or augmenting a muscle in mammals. In the case of the artificial tendon, a tendon of a fin taken from a fish can be used for replacing an injured tendon in mammals. In the case of the artificial cartilage, a vertebral or intervertebral cartilage taken from a fish can be used for replacing an injured joint cartilage in mammals. The alimentary canal from the stomach to intestine may be used as the artificial alimentary canal tissue (e.g. an artificial esophagus) or an alternative to trachea. Although the livers of Chondrichthyes, Osteichthyes and Cyclostomata differ from the human liver in types of metabolic isozyme, they may be used as the artificial liver tissue without any problem on detoxication. The artificial pancreas tissue may be used for producing insulin by direct implantation of a fish-derived pancreatic parenchymal tissue including Langerhans"" islands into a hemostatically cut opened-pocket in a mammalian recipient""s pancreas. In the case of the artificial spleen tissue, a splenic parenchymal tissue taken from a fish may be cut into 1 cm cubes and implanted into a hemostatically cut opened-pocket in a mammalian recipient""s spleen. In the case of the artificial liver or pancreas, a hepatic or pancreatic parenchymal tissue taken from a fish may be similarly cut into 1 cm cubes and implanted into a hemostatically cut opened-pocket in a mammalian recipient""s liver or pancreas. In the case of the artificial kidney tissue, a renal parenchymal tissue taken from a fish may be similarly cut into 0.5 cm cubes and implanted into a hemostatically cut opened-pocket in a mammalian recipient""s kidney. In the case of the artificial heart tissue, a heart tissue taken from a fish may be shaped into a 2 cm square and sewn to a mammalian recipient""s heart from which necrosed muscles have been removed. As the artificial blood vessel, an aorta of a fish may be used for transplantation. In the case of a nerve, the spinal cord of the Cyclostomata has a length of about 20 cm and may be used as the artificial nerve tissue to replace a broken nerve. In the case of the artificial brain tissue, a brain tissue taken from a fish may be cut into 3 mm cubes and implanted into a mammalian recipient""s head in which a part of the brain has been injured, necrosed or lost. The alimentary canal may also be used as the artificial blood vessel, from which an intima has been removed and which is turned over before used.
The artificial cornea, artificial muscle tissue, artificial tendon, artificial cartilage, artificial alimentary canal tissue, artificial liver tissue, artificial pancreas tissue, artificial spleen tissue, artificial kidney tissue, artificial heart tissue, artificial blood vessel, artificial nerve tissue and artificial brain tissue thus obtained can be rapidly fused with living tissues because of its non-antigenicity without HLA (human leukocyte antigen), and therefore, a scar will not be prominent.
The biomaterials of the present invention can be subjected to a sterilization process by cooling at xe2x88x9260xc2x0 C., washing with saline, washing with a saline solution containing an antibiotic and then soaking them in recipient""s blood after being shaped into a suitable shape used as the artificial cornea, artificial muscle tissue, artificial tendon, artificial cartilage, artificial alimentary canal tissue, artificial liver tissue, artificial pancreas tissue, artificial spleen tissue, artificial kidney tissue, artificial heart tissue, artificial blood vessel, artificial nerve tissue, artificial brain tissue, and the like. They can also be stored aseptically at a low temperature. Accordingly, the biomaterials of the present invention are also preferable in view of these aspects.
The biomaterials of the present invention have a prolonged storage life of about 6 months in saline or seawater at xe2x88x9260xc2x0 C. Accordingly, the biomaterials of the present invention can be sufficiently provide when there is a sudden need for them.
Unlike the conventional materials derived from bovine or human, the biomaterials of the present invention have no risk of viral infection and are stably provided. They are the preferred alternatives to the above conventional biomaterials and transplantable organs.